The candidate is currently a postdoctoral research fellow in the division of Hematology-Oncology at the New England Medical Center, and an Instructor in the Department of Medicine. Training subsequent to Internal Medicine Internship and Residency has included a productive 6 month research fellowship at the royal Postgraduate Medical School in London, a year of clinical fellowship training in Hematology-Oncology, and thus far 2 1/2 years of research fellowship in the field of molecular oncology. While studying a 32 kb segment of DNA immediately upstream of the HRAS1 locus, he has tentatively identified 2 and possibly 3 genes associated with CpG islands. Preliminary expression studies indicate the possibility of coordinate regulation of genes in the cluster. In addition, Southern hybridization experiments suggest cross-hybridization to a small family of related genes of unknown map position. The broad, long-term objectives of this proposal are to examine the molecular genetic organization and significance of this HRAS1 gene cluster, and to study whether alterations of these genes have a role in the development of cancer. In the initial phases of the project the boundaries and elements of the HRAS1 gene project is to clone a large region of DNA surrounding HRAS1 and search for candidate gene sequences, as genetic data indicate the HRAS1 (or its associated VTR) is either directly involved in tumorigenesis, or is in close proximity to a putative tumor suppressor gene locus. He will determine whether the association of structural changes or deletions of this region seen in several tumor types is due to alterations of genes in the HRAS1 cluster or others in the region. The isolation and characterization of genes within the HRAS1 cluster will lead to a better understanding of how these genes contribute to normal cell growth and to the pathology underlying the development of cancer. The experiments will be performed in the newly renovated, well equipped, Tupper Research Institute at the New England Medical Center. The work will be done under the guidance of Theodore G. Krontiris M.D., Ph.D., and has the support of other members of the faculty in the Division of Hematology- Oncology and the Departments of Medicine, Molecular Biology and Microbiology.